Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJS0T2B)

• DOT Name: Transcriptional enhancer factor TEF-3 (TEAD4)
• Synonyms: TEA domain family member 4; TEAD-4; Transcription factor 13-like 1; Transcription factor RTEF-1
• Gene Name: TEAD4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Atypical teratoid/rhabdoid tumour
  Brain neoplasm
  Colorectal adenoma
  Endometrial carcinoma
  Gastric cancer
  Gonorrhea
  Leukocyte adhesion deficiency type 1
  Lung adenocarcinoma
  Medulloblastoma
  Neoplasm
  Advanced cancer
  Colorectal carcinoma
  Head-neck squamous cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  HER2/NEU overexpressing breast cancer
  Arrhythmia
  Bladder cancer
  Chronic obstructive pulmonary disease
  Cutaneous melanoma
  Glioblastoma multiforme
  Melanoma
  Neuroblastoma
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: TEAD4_HUMAN
• PDB ID: 5GZB; 5NO6; 5OAQ; 6GE3; 6GE4; 6GE5; 6GE6; 6GEC; 6GEE; 6GEG; 6GEI; 6GEK; 6HIK; 6Q2X; 6Q36; 6SEN; 6SEO; 8A8R; 8C17; 8CAA
• Pfam ID: PF01285 ; PF17725
• Sequence:
  MEGTAGTITSNEWSSPTSPEGSTASGGSQALDKPIDNDAEGVWSPDIEQSFQEALAIYPP
  CGRRKIILSDEGKMYGRNELIARYIKLRTGKTRTRKQVSSHIQVLARRKAREIQAKLKDQ
  AAKDKALQSMAAMSSAQIISATAFHSSMALARGPGRPAVSGFWQGALPGQAGTSHDVKPF
  SQQTYAVQPPLPLPGFESPAGPAPSPSAPPAPPWQGRSVASSKLWMLEFSAFLEQQQDPD
  TYNKHLFVHIGQSSPSYSDPYLEAVDIRQIYDKFPEKKGGLKDLFERGPSNAFFLVKFWA
  DLNTNIEDEGSSFYGVSSQYESPENMIITCSTKVCSFGKQVVEKVETEYARYENGHYSYR
  IHRSPLCEYMINFIHKLKHLPEKYMMNSVLENFTILQVVTNRDTQETLLCIAYVFEVSAS
  EHGAQHHIYRLVKE
• Function: Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. Acts by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction. Binds specifically and non-cooperatively to the Sph and GT-IIC 'enhansons' (5'-GTGGAATGT-3') and activates transcription. Binds to the M-CAT motif.
• Tissue Specificity: Preferentially expressed in skeletal muscle. Lower levels in pancreas, placenta, and heart.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway:
  RUNX3 regulates YAP1-mediated transcription (R-HSA-8951671)
  Formation of axial mesoderm (R-HSA-9796292)
  Zygotic genome activation (ZGA) (R-HSA-9819196)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Atypical teratoid/rhabdoid tumour	DIS1FA0D	Strong	Altered Expression	[2]
Brain neoplasm	DISY3EKS	Strong	Altered Expression	[2]
Colorectal adenoma	DISTSVHM	Strong	Altered Expression	[3]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Gonorrhea	DISQ5AO6	Strong	Biomarker	[6]
Leukocyte adhesion deficiency type 1	DISA1J7W	Strong	Biomarker	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[10]
Stomach cancer	DISKIJSX	moderate	Posttranslational Modification	[11]
HER2/NEU overexpressing breast cancer	DISYKID5	Disputed	Biomarker	[12]
Arrhythmia	DISFF2NI	Limited	Biomarker	[13]
Bladder cancer	DISUHNM0	Limited	Biomarker	[14]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[15]
Cutaneous melanoma	DIS3MMH9	Limited	Genetic Variation	[16]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[17]
Melanoma	DIS1RRCY	Limited	Genetic Variation	[16]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[18]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[14]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[14]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Transcriptional enhancer factor TEF-3 (TEAD4).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Transcriptional enhancer factor TEF-3 (TEAD4).	[30]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[24]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[25]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[24]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[27]
Rofecoxib	DM3P5DA	Approved	Rofecoxib increases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[28]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol decreases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Transcriptional enhancer factor TEF-3 (TEAD4).	[32]

References

• [1] Glucocorticoid Receptor Signaling Activates TEAD4 to Promote Breast Cancer Progression.Cancer Res. 2019 Sep 1;79(17):4399-4411. doi: 10.1158/0008-5472.CAN-19-0012. Epub 2019 Jul 9.
• [2] Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor.Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26398. Epub 2016 Dec 14.
• [3] TEAD4 promotes colorectal tumorigenesis via transcriptionally targeting YAP1.Cell Cycle. 2018;17(1):102-109. doi: 10.1080/15384101.2017.1403687. Epub 2018 Jan 4.
• [4] Tead and AP1 Coordinate Transcription and Motility.Cell Rep. 2016 Feb 9;14(5):1169-1180. doi: 10.1016/j.celrep.2015.12.104. Epub 2016 Jan 28.
• [5] High Yes-associated protein 1 with concomitant negative LATS1/2 expression is associated with poor prognosis of advanced gastric cancer.Pathology. 2019 Apr;51(3):261-267. doi: 10.1016/j.pathol.2019.01.001. Epub 2019 Feb 25.
• [6] Verteporfin targeting YAP1/TAZ-TEAD transcriptional activity inhibits the tumorigenic properties of gastric cancer stem cells.Int J Cancer. 2020 Apr 15;146(8):2255-2267. doi: 10.1002/ijc.32667. Epub 2019 Sep 30.
• [7] TEAD4 exerts pro-metastatic effects and is negatively regulated by miR6839-3p in lung adenocarcinoma progression.J Cell Mol Med. 2018 Jul;22(7):3560-3571. doi: 10.1111/jcmm.13634. Epub 2018 Apr 18.
• [8] Computational insights into the interaction mechanism of transcription cofactor vestigial-like protein 4 binding to TEA domain transcription factor 4 by molecular dynamics simulation and molecular mechanics generalized Born/surface area) calculation.J Biomol Struct Dyn. 2019 Jul;37(10):2538-2545. doi: 10.1080/07391102.2018.1491889. Epub 2018 Nov 9.
• [9] A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer.Mol Cell. 2019 Aug 22;75(4):791-806.e8. doi: 10.1016/j.molcel.2019.06.010. Epub 2019 Jul 11.
• [10] TEAD4 overexpression promotes epithelial-mesenchymal transition and associates with aggressiveness and adverse prognosis in head neck squamous cell carcinoma.Cancer Cell Int. 2018 Nov 12;18:178. doi: 10.1186/s12935-018-0675-z. eCollection 2018.
• [11] Epigenetic silencing of miR-1271 enhances MEK1 and TEAD4 expression in gastric cancer.Cancer Med. 2018 Jul;7(7):3411-3424. doi: 10.1002/cam4.1605. Epub 2018 Jun 4.
• [12] Identification of key genes involved in HER2-positive breast cancer.Eur Rev Med Pharmacol Sci. 2016;20(4):664-72.
• [13] Transcription enhancer factor-1-related factor-transgenic mice develop cardiac conduction defects associated with altered connexin phosphorylation.Circulation. 2004 Nov 9;110(19):2980-7. doi: 10.1161/01.CIR.0000146902.84099.26. Epub 2004 Nov 1.
• [14] Metformin targets a YAP1-TEAD4 complex via AMPK to regulate CCNE1/2 in bladder cancer cells.J Exp Clin Cancer Res. 2019 Aug 27;38(1):376. doi: 10.1186/s13046-019-1346-1.
• [15] Expression of Hippo pathway genes and their clinical significance in colon adenocarcinoma.Oncol Lett. 2018 Apr;15(4):4926-4936. doi: 10.3892/ol.2018.7911. Epub 2018 Jan 31.
• [16] Genetic variants in Hippo pathway genes YAP1, TEAD1 and TEAD4 are associated with melanoma-specific survival.Int J Cancer. 2015 Aug 1;137(3):638-45. doi: 10.1002/ijc.29429. Epub 2015 Jan 28.
• [17] Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma.Nat Commun. 2018 Oct 1;9(1):4020. doi: 10.1038/s41467-018-06258-2.
• [18] Cross-Cohort Analysis Identifies a TEAD4-MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma.Cancer Discov. 2018 May;8(5):582-599. doi: 10.1158/2159-8290.CD-16-0861. Epub 2018 Mar 6.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [23] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [24] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [25] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [26] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [29] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [30] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.